JUST THINK. Without real lives, all that hard work sequencing
the human genome will be worthless. In order to tease out the
roots of disease-genetic and envirorunental-researchers will need
not only people's DNA but also their medical records, details
of their lifestyles and, preferably, family histories. And with
the imminent arrival of the first sequenced human genome, there's
a race on to create large databases to hold all that information.
This week, Britain's Medical Research Council (MRC) outlined just
such a database, starting with 500 000 volunteers. At the same
time, a British company called Gemini Holdings announced plans
for another database covering the Canadian province of Newf6undland
and Labrador. Iceland is already some way down the road to a national
database, but is now running into problems. It should be possible
to learn from its troubles. just over a year ago, as the parliament
in Reykjavik discussed the database, New Scientist argued for
a cautious approach. Unfortunately, the worst has happened. The
Icelandic govemment has not taken all its people with it. Doctors
feel the database threatens their relationships with patients
and are threatening to sabotage it by withholding medical records
("Cuts no ice", New Scientist, 12 February, p 5). Let's
be clear: these databases are essential. They promise to reveal
"harmful" genes and, in some cases, ways for carriers
to stave off the worst effects of those genes. They will also
help companies to develop drugs more efficiently. So, it is crucial
that people feel at ease with the implications of researchers
rifling through their DNA. One issue still to be resolved is consent.
Iceland's 270 000 citizens are automatically included in the project.
If they do not want to be involved, they have to opt out. This
seems harsh. Certain genes will have serious powers of prediction-of
early-onset Alzheimer's, for example-which have big implications
for individuals and their families. People need to understand
that as well as benefits, the new databases will atso bring bad
news-then they should be asked if they want to take part. Allied
to consent is the question of who decides what research may-be
done with a database. Medical research is one thing, but there
are scientists eager to study the genetic roots of intelligence,
criminality and even race. Should donors have the freedom to withdraw
their DNA from such potentially divisive projects? Privacy is
another problem. The databases cannot be made fully anonymous.
As people fall ill and die, the details will need to be added.
So, safeguards must be included to prevent people being identified
on the database. This has been another bone of contention in Iceland.
Then there is the question of who benefits. The databases are
potential gold mines for drugs companies. But they should not
be the only ones to profit. Iceland has transferred ownership
of its database to deCODE genetics, a private company in Reykjavik-a
move that is being challenged by a group of doctors as unconstitutional.
deCODE has already signed a $200 million deal with Swiss pharmaceuticals
company Hoffmann-La Roche to let it use the database. In return
for the nation's DNA, deCODE will supply Iceland with any drugs
developed from the database free of charge. In a similar deal,
Gemini has agreed to pay royalties on any commercial developments
from its database to a foundation for the benefit of the people
of Newfoundland and Labrador. Are these reasonable retums for
the wealth the databases will generate? Britain's database will
initially be operated by the MRC and the Wellcome Trust, two organisations
that plough profits back into biomedical research. What happens,
though, if they decide to sell off this lucrative product? The
MRC has this week appointed a company to measure the public's
response to its plans. This is a good start, but it does not go
far enough. Somebody needs to look hard at the roles of the MRC
and Wellcome Trust in this project. What responsibilities will
they have to the public? These issues deserve a full and wide
public debate, mediated by an independent body, such as the Nuffield
Council for Bioethics or the goverrunent's Human Genetics Advisory
Commission. The government of Newfoundland and Labrador, which
is only now formulating a policy on genetic testing, should also
make sure that a debate takes place on Gemini's plans. These databases
are likely to have a profound impact on the nation's health. They
are too important to get wrong.

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EVER wondered why listening to loud music or singing at the
top of your voice is such fun? Scientists at the University of
Manchester say a pleasure-inducing hearing mechanism we've inherited
from our fishy ancestors could be to blame. A team led by psychologist
Neil Todd, an expert in music perception, has discovered that
the sacculus, an organ forming part of the balance-regulating
vestibular system in our inner ear, is tuned in to respond to
sound frequencies that predominate in music-despite the fact that
the sacculus is not thought to have any hearing function. Even
more curious, says Todd, our saccular frequency sensitivity appears
to mimic that of fish-the only type of creature known to use its
sacculus for hearing. "This primitive hearing mechanism from
our vertebrate ancestors appears to have been conserved as a vestigial
sense in humans," says Todd. Because the vestibular system
has a connection to the hypothalamus, the part of the brain responsible
for drives like hunger, sex and hedonistic responses, Todd believes
that people might be getting a pleasurable buzz when they listen
to music-which could explain why music has developed into such
a cultural force. This buzz may mimic the thrills people get from
swings and bungee jumping, where motion stimulates the balance
centre. But there is a proviso: the sacculus only appears to be
sensitive to loud volumesabove 90 decibels. Despite this, crooners
could also love their own singing because sound levels in the
larynx have been estimated to be as high as 130 decibels. "It's
bloody loud in there," Todd says. Because the sacculus is
buried deep within the ear (see Diagram), Todd and his colleagues
Frederick Cody and Jon Banks could not measure its reaction to
sound directly. But in regulating balance-particularly head posture-the
sacculus evokes electrical signals in certain neck muscles. So
the team exploited this by asking students to tense their neck
muscles, and using surface electrodes, they measured the extra
signals produced when the sacculus responds to sound rather than
balance. In tests, 11 students listened to tone pips of varying
frequencies. Their saccular sensitivity ranged from 50 hertz up
to 1000 hertz, with a peak between 300 and 350 hertz. On the musical
scale, middle C is 261 hertz; male and female voices have frequency
ranges up to 200 and 400 hertz respectively. The researchers will
publish their results this spring in a forthcoming edition of
the journal Hearing Research. "The distribution of frequencies
that are typical in rock concerts and at dance clubs almost seem
designed to stimulate the sacculus. They are absolutely smack
bang in this range of sensitivity," Todd says. Large groups
of people singing or chanting together, such as a choir or a crowd
at a sporting event, could also trigger the mechanism, he adds.
Paul Marks

Toxic wave NS
19 Feb 2000

ONE hundred tonnes of cyanide in the water that spilled from
a Romanian goidmine have devastated rivers in central Europe,
say Hungarian scientists. A breach of a dam at the Baia Mare goldmine,
near Oradea in northwest Romania, on 30 January has wiped out
fish and other aquatic life for hundreds of kilometres along the
River Tisza in Hungary. By early this week the pollution had reached
the Danube in Serbia and was concentrated enough to kill fish.
Cyanide is used by miners to separate gold and sliver from other
ores. As little as 0-1 milligrams per litre of water can be fatal
to fish. Scientists from Vituki, the state-owned water research
centre in Budapest, monitored the toxic wave from the mine as
it flowed through Hungary. After 10 days they found that the cyanide
had not broken down significantly. However, the cyanide is being
diluted as the wave travels downstream, says Ferec Laszlo from
Vituki. When the poison crossed the border into Hungary there
were 30 milligrams of cyanide per litre, 10 days later the level
had fallen to 1-5 mg/i as the water left the country. More than
300 tonnes of dead fish have been removed from Hungarian rivers,
while invertebrate and crustacean populations have been wrecked.
Laszlo is worried about the long-term damage to the ecosystem.
"it is the biggest release of cyanide I am aware of,"
he says. "it is disastrous." Rob Edwards

The hole story? Plankton
are escaping the ravages of ozone depletion-so far

NS 19 Feb 2000

THE ozone hole above Antarctica may not be damaging life in
the ocean below after all. If Californian researchers are right,
then increased ultraviolet radiation is having scarcely any effect
on the growth of marine plankton, the base of the ocean's food
chain.

The team, led by Kevin Arrigo of Stanford
University in Palo Alto, has created computer models of phytoplankton
growth over a year in the southern hemisphere before and after
the ozone hole appeared in the 1980s. They included such factors
as the position of the ozone hole, cloud cover, and UV-B strength,
the type of ultraviolet radiation that increases as atmospheric
ozone declines. To find out what increased UV-B did to phytoplankton,
the researchers compared two models: one based on data from 1992,
a year with a yawning ozone hole and the other with the same parameters
except for the ozone levels, which were taken from 1978, a year
of 'normal" conditions before the hole appeared. Over the
southern hemisphere ecosystem as a whole, they found that primary
phytoplankton production decreased by only about 1 per cent in
1992, which is significantly lower than other estimates. Arrigo's
work does not discount the results of a number of studies showing
fliat increased UV-B can stunt phytoplankton growth by 10 per
cent or more in localised areas or in the laboratory (New Scientist,
8 August 1998, p 24). The difference is that his study looked
at the big picture of LTV-B for the whole ocean. In previous studies,
researchers scaled up measurements of plankton growing beneath
the hole and elsewhere to calculate an overall effect for the
whole Southern Ocean. But although they knew that factors such
as cloud cover were important, they are difficult to include in
such calculations. "On a cloudy day under a deep hole, there's
still not nearly as much UV flux as on a clear day with no hole,"
says Arrigo. Another important factor is that, at any given time,
around 80 per cent of the southem hemisphere's ozone hole is over
ice. So only a small fraction of phyto-plankton in Southem Ocean
waters feels the full brunt of ozone depletion, he says. Both
these factors were incorporated into the new models. Raymond Smith,
at the University of Califomia, Santa Barbara, who did landmark
research on the effect of increased UV-B on phytoplankton, says
that marine plankton have adapted to cope with the hole. "It's
obvious that [the impact] isn't going to be catastrophic,"
he says. "We've had the ozone hole for a decade and a half
and the system is still there." Although Arrigo's results
are good news, he says we shouldn't stop worrying about ozone
depletion, because phytoplankton is only one component of the
ecosystem. "There may be species shifts going on that no
one is aware of," he says. And we shouldn't forget that Southem
Ocean phytoplankton could be stretched to their limit in absorbing
ultraviolet radiation. 'Right now, they're keeping up,' he says,
'but if the problem gets worse who knows?" Mark Schrope

Precious Junk NS 19 Feb 2000

Garbage DNA has its uses

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SOMETHING strange is going on. Viruses all over the world are
preserving a stretch of genetic material that until now was considered
redundant. Given that DNA with no function tends to change rapidly
because of random mutation, this suggests that this particular
piece of "junk" DNA must be of some use to the viruses.
Jim Van Etten and his colleagues at the University of Nebraska
found the mysterious sequence within a gene carried by chlorella
viruses. These viruses live in algae in lakes around the world,
and the gene the Nebraska team was studying repairs damage to
viral DNA caused by ultraviolet light. Non-coding DNA sequences
inside genes are called introns. These are generally considered
junk DNA, containing no useful information. They tend to change
more rapidly than protein-coding DNA because they are npt under
any selective pressure to hang on to@ useful sequence. Even the
few introns that do have functions-such as jumping into other
genes-only conserve a limited amount of genetic material.

The Nebraska scientists determined the DNA sequence of the
repair gene from 42 chlorella viruses isolated over a period of
12 years from the US, China, Australia and Argentina. They found
that 15 of the viruses shared an identical copy of the intron.
Another four viruses contained almost exact copies of a related,
but slightly smaller intron. "I don't know of any other examples
of this type of intron sequence conservation. There has to be
selective pressure to maintain the sequence with that kind of
fidelity," says Van Etten. "There's something unusual
going on here," agrees Arlin Stoltzfus of the Center for
Advanced Research in Biotechnology in Maryland. He thinks that
the intron sequence could be identical in the viruses simply because
it has spread though the virus population recently and has not
yet had time to mutate. But such a rapid spread implies that the
intron must be conferring some selective advantage. This doesn't
have to be the case, however. David Penny, a theoretical biologist
at Massey University in New Zealand, thinks that the intron could
be compared to a "selfish gene", good at ensuring its
own survival without necessarily benefiting the virus. "What
is good for a particular gene need not be best for the individual
that houses the gene," he says. Joanna Marchant

Roots of immunity NS 19 Feb 2000

When it comes to fighting disease, you are more like, a plant
than you think, says Trisha Gura

IN THE early 1970s, a mysterious epidemic hit several hospitals
in California. Infections-most of them blood-borne or respiratory-were
sweeping through the wards, but doctors and public health officials
couldn't put their finger on the source. In desperation, they
enlisted the help of a team of infectious disease specialists
at the University of California, Berkeley. After a careful search,
the microbial detecfives reached a startling conclusion. The epidemic
was caused by a plant disease-a bacterium called Pseudomonas aeruginosa
that infected both the flowers brought in to cheer up sick patients
and the salads and vegetables on their plates. Amazingly, the
same bacterium that attacked the plants was also causing illness
in people. For the next two decades, scientists regarded this
as no more than a curious one-off. But in the past few years,
the parallels uncovered between plant and animal disease have
spread far beyond Pseudomonas. The pathogens that cause sickness
in these two'disparate kingdoms of life are turning out to use
much the same molecular machinery-and their hosts use remarkably
similar countermeasures. Because of these striking similarities,
researchers are now looking to our green cousins to leam more
about diseases that afflict people. Using knowledge and techniques
developed in plants, they are beginning to search for previously
unsuspected disease-resistance genes lurking in the genomes of
mammals. And others are importing weapons from the plants' disease-fighting
arsenal to see if they might someday work in people. Such cross-fertilisation
would have been regarded as heresy only five years ago, when there
seemed to be an unbridgeable gulf between the worlds of plant
and animal microbiology. Plant researchers focused on agricultural
applications such as finding diseaseresistance genes, studying
them and breeding them into crops, while medical researchers addressed
the cell biology of disease. But suddenly, the medical people
have gained a new-found respect for the secrets their plant colleagues
can reveal about animal diseases. In particular, plant biologists
have long understood the struggle between pathogen and host as
a gene-on-gene duel. Many bacteria target their hosts via virulence
factors encoded by Avr genes (short for "avirulence",
ironically, because they were discovered in strains rendered ineffective
by mutation). Plants parry this attack by evolving resistance
factors produced by R genes, then pathogens respond with new genes,
and so on. Over the years, plant pathologists have identified
many of the genes involved by bombarding virulent microbes with
X-rays or chemicals that mutate their DNA at random. The resulting
mutants are then let loose on healthy hosts. Those microbes that
can't infect plants, or do so only weakly, have probably picked
up mutations in genes that encode crucial virulence factors. Animal
researchers hadn't approached disease pathogens that way until
the plant-animal similarities began coming to light. "It
taught the animal people that they n-dght be missing the tip of
the iceberg by only focusing on normal infection. Disease resistance
is really an abnormal infection," says Jeff Dangl, a plant
geneticist at the University of North Carolina at Chapel Hin.
By studying such failed infections, medical researchers n-dght
find virulence genes that disease-causing bacteria use to attack
humans, and develop antibiotic drugs to blunt the attack. But
spotting the genes responsible for virulence and resistance in
animals is a daunting task. It would take at least 30 000 mutants
to systematically comb the entire genome of P aeruginosa for all
possible virulence factors made by the bug, estimates Lory Rahme,
a plant pathologist tumed molecular microbiologist at Harvard
Medical School in Boston. Test each mutant on 10 host animals-to
make sure the result is statistically significant-and you are
faced with a screening nightmare if the hosts are, say, niece.
But even that is not enough. You'll want to go still further and
systematically test the mutated pathogens in several strains of
mutated hosts. "In animals, it would simply be impossible,"
Rahme concludes. But maybe there's an easier way. in 1992, Rahme,
who was searching for a postdoctoral project, turned to Milt Schroth,
a plant pathologist at the University of Cafifomia at Berkeley.
-Why not start in plants and move to animals?" she proposed.
Schroth, a member of the team that first collared Pseudomonas
in the hospital infections 20 years earlier, gave her the 80 or
so Pseudomonas isolates he had saved from that investigation.
Rahme took those to Boston, where she teamed up with microbiologist
Frederick Ausubel at Harvard and Ronald Tompkins,-chief of staff
at Shriners Bums Hospital. Together, they set up a massive screening
system that begins in mustard plants, moves through flies and
nematode worms, and ends up in mice. T'he researchers start by
randomly mutating lots of P. aeruginosa and then squirting the
altered bacteria onto the leaves of mustard plants. Any bugs har
bouring mutations in crucial virulence factors will be unable
to grow or repro duce as effectively as the normal microbes, which
infect the plants with ease. The team then picks out these Pseudomonas
duds and injects them into fruit flie@which normal Pseudomonas
can also attack-to see if they are impotent in this host, too.
The least infective bacterial mutants also pass through Ausubel's
lab, where investiga tors test their virulence in worms and, across
the street, to Tompkins's lab, where the mutant Pseudomonas strains
are screened in mice that are especially susceptible to infections.

Attack genes

So far, the researchers have divided the mutants into eight
classes according to which combination of hosts the putative virulence
factors target. For example, one class carries mutations in genes
that, if nor mal, would help to infect mustard plants and fruit
flies and nothing else. Another class carries mutations in genes
that work in plants, worms and mice, but not flies. Right now,
Rahme and her colleagues are concentrating on a group of 24 pron-dsing
virulence gene candidates that control the severity and persistence
of infection in at least three of the four groups. In fact, half
of those 24 genes work in an four hosts, Rahme reported in December
at a collo quium on plant-animal disease s ties in Irvine, Calfforriia,
hosted by the National Academy of Sciences. The researchers have
located the genes where these 24 mutations reside and are now
trying to figure out what the genes actually do. "We are
getting out information on what mechanisms of infection may be
universal and what may t be host-specific," says Rahme. At
least some of the genes produce something called the Type III
secretion system@ssentially a molecular syringe made up of 30
or so proteins that some bacteria use to inject toxins or other
mol ecules into host cells. Some of the syringe pieces-the ones
responsible for pumping the toxins or molecules out of the bacter
ial cell-are so universal that last year, t geneticists found
they could mix and match genes from plant and animal s pathogens
without affecting the working of the syringe (Proceedings of the
National Academy of Sciences, vol 96, p 12 839). Sure enough,
back in 1995 Rahme's team had reported that a syringe protein
proy duced by one of a class of genes known as hrp genes is necessary
to make Pseudomonas virulent in both plants and mice (Science,
vol 268, p 1899). Since then, the researchers have found several
more hrp genes among their 24 most widely active virulence genes.
Within two years or so, they hope to begin testing drugs to block
these virulence factors-perhaps using plants, rather than mice,
for the initial screening process. VVhat about the other side
of the cointhe hosts' defences? Mammals, like plants, seem to
have genes affecting their susceptibility to certain pathogens.
For example, a mutation in a certain strain of mice prevented
them from being kihed,by a mutant strain of Bordetella bronchiseptica,
which usually causes respiratory tract infections in many mammals,
Jeff Miller of the University of California at Los Angeles told
researchers at last December's colloquium. The interaction looks
remarkably like the gene-for-gene thrust and parry familiar to
plant disease specialists. But plants and people share an even
deeper similarity in their response to invading germs-an ancient
immune system handed down from our common ancestor hundreds of
millions of years ago. Here's how it works in plants: a pathogen
attacks a plant tissue and unwittingly emits a signal that is
picked up by a protein encoded by a resistance gene. Most R-genes
encode receptors, and many of these closely resemble a receptor
first discovered in fruit flies called Toll, which also orchestrates
the immune response in insects. Once triggered, the R-gene response
branches into two pathways (see Diagram, p 28). At the site of
infection, an enzyme called MAP kinase kicks off a cellsuicide
program called the hypersensitivity response, which involves the
release of nitric oxide, a gaseous signal molecule. In the second
pathway, the gas works in concert with salicylic acid to circulate
throughout the plant and eventually unleash an army of antimicrobial
molecules well beyond the infection site, says Daniel luessig
of Rutgers University in Piscataway, New Jersey. The whole process
is almost identical to the inflammatory response of mammals. When
a pathogen attacks or a tissue is injured, mammalian cells release
tumour necrosis factor, a signal that binds to a Tolllike receptor
called the interleukin-1 receptor. This receptor triggers a MAP
kinase that initiates a cen-suicide program called apoptosis.
And this is mediated by-you've guessed it-nitric oxide. The camage
that results is familiar as the pus that fills an inflamed wound.
The kinase also flicks on cell signalling molecules that enter
the circulation and trigger the release of potent inflammatory,
clotting and antimicrobial agents.

"To me, the hypersensitivity response is an abscess in
plants," says Carl Nathan, an immunologist at Cornell University's
Weill Medical College in Ithaca, New York. Until last December,
Nathan admits, he hadn't paid any attention to the plant phenomenon.
"I had read about it but never seen it. When I did, I was
blown away by the similarity."

Tuberculosis clue

Indeed, Nathan and others now think mammals might carry specific
resistance genes that-like the R genes of plantsrecognise classes
of germs and spur a generalised inflammatory response to deal
with the invaders before the more specialised immune system-based
on antibodies and T-cells-can kick in. Nathan had already teamed
that mutations in a gene for an enzyme caned nitric oxide' synthase-II
(or drugs that block the enzyme) render mice susceptible to some
pathogens, such as the tuberculosis bacterium, that they would
normally resist. Something similar may occur in people. Nathan
estimates that 90 per cent of people infected with TB never show
signs of the disease unless they become malnourished or immunosuppressed.
"VVhat is it about the unlucky 10 per cent that renders them
susceptible?" he asks. The answer could be variations in
specific genes. Already, Nathan has found a number of candidate
genes and is mutating them in mice to see what their contribufion
to the disease might be. So if plants have cell death and signalling
pathways similar to those in animals, might the two respond to
the same drugs? The answer is an emphatic yes. In people, aspirin
(acetylsalicylic acid) has long been known to relieve inflammation
by blocking prostaglandin production. Its parent, salicylic acid,
was first isolated from the bark of willow trees, where it enhances
defence by aiding the signalling role of nitric oxide. Those seem
like opposite effects, but plant researcher Bud Ryan at Washington
State University in Pullman has an explanation. Plants crank up
salicylic acid production when attacked by microbes. Salicylic
acid then shuts down the plant's production of jasmonic acid,
which would otherwise signal the production of protease inhibitors
and cross-@king agents that prevent insects from digesting its
tissues (left branch in Diagram), in favour of the hypersensitivity
response (right branch in Diagram). In other words, when faced
with both threats, the plant focuses all its energies on dealing
with the microbe. In people, aspirin blocks the same pathway of
inflammation, probably targeting at least two enzymes similar
to those that it blocks in the plant pathway.

Rethinking aspirin

But plant researchers know that salicylic acid plays many other
roles in plants. Klessig speculates that aspirin may likewise
act through a variety of similar mechanisms in people. If so,
plants may shed new light on one of medicine's star performers.
The close parallel between plant and animal defence systems may
yield other useful drugs. Intriguingly, in 1996, Ryan's group
found that ultraviolet light activates the defensive response
in plants just as it does in humans. So perhaps compounds such
as flavonoids-which protect the plant against ultraviolet light-might
also serve as anti-inflammatory drugs for people. Likewise, Klessig
and other researchers are studying a class of broad-spectrum plant
antibiotics called phytoalexins that they hope may also work in
animals. Conversely, the synthetic anti-tumour drug suramin-which
can prevent LTV light from causing inflammation in humansalso
blocks the wounding response of tomato plants, Ryan's group has
found, in research to be published this spring in the Proceedings
of the National Academy of Sciences. Suramin is extremely toxic
to patients in its present form, but if pharmacologists can find
ways to mitigate its side effects, they may be able to find other
uses for the drug. With so many similarities emerging between
diseases of plants and peopleinterchangeable molecular syringe
parts, related receptors and signals, and pathogens that can infect
species in both kingdomsresearchers say there must have been an
ancient, common ancestor that passed down the crucial pieces of
a basic immune response.

Carbon copies: animals and plants use nearly identical systems
to fight off pathogens

"The cogs are the same, but how they are connected up
is different in different species," says plant pathologist
Jonathan Jones at the John hines Centre in Norwich, who studies
Toll-like receptors.

So it's no surprise that pathogens have similar parts-relics
of the diseases that afflicted our common ancestor hundreds of
millions of years ago. This brings a fresh unity of purpose to
plant and animal disease experts. "The key is animal people
have strengths that we don't have, and we have strengffis that
they don't have," says Dangl. "It's always good to look
at your problem from a slightly oblique viewpoint." Plant
and animal pathologists know this only too well, as they discover
that all along, they have been unwittingly reading from the same
page of the Book of Life.

Trisha Gura is a science writer in Cleveland, Ohio

Further reading: 'Novel antimicrobial targets from combined
pathogen and host genetics' by Carl Johnson and Leo Liu, Proceedings
of the National Academy of Sciences, vol 97, p 101 7